This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nonalcoholic fatty liver disease (NAFLD) is a common and increasingly recognized disorder characterized by macrovesicular accumulation of fat in hepatocytes, usually found in association with obesity, insulin resistance, and hyperlipidemia. This condition occurs in both adults and children, and arguably represents the most common cause of liver disease in pre-adolescence and adolescence. Insulin resistance and oxidative stress are considered to be the two most important mechanisms in the pathogenesis of NAFLD. We hypothesize that metformin and vitamin E will lead to sustained reduction in serum ALT with biopsy proven NASH through changes in insulin resistance or oxidative stress. The principal objective of this randomized, multicenter, double-masked, placebo-controlled trial is to evaluate whether 96 weeks of treatment with either metformin of vitamin E leads to sustained reduction in serum ALT in nondiabetic children with NAFLD compared to treatment with placebo. Other objectives include: To evaluate changes in serum AST and GGT To measure change in histologic feature scores of NAFLD To evaluate change in liver fibrosis, inflammation, or steatosis To evaluate change in insulin resistance indices To evaluate change in serum vitamin E levels To evaluate change in serum cytokine and fibrosis marker levels o To evaluate change in serum lipid profile To evaluate changes in anthropometric measurements (weight, BMI, waist to hip ratio, waist circumference, triceps skin fold thickness, total body fat, and distribution of fat) To measure change in quality of life scores To assess the role of diet and activity in the development and treatment of NAFLD To elucidate the natural history regarding clinical course and histology in untreated pediatric NAFLD (placebo plus diet and exercise advice) To obtain serum, liver, and DNA specimens from biopsy-confirmed pediatric patients with NAFLD for subsequent studies on etiopathogenesis. This NIH funded, multi center, Phase IV, drug trial has been recruiting patients since August of 2005 at eight institutions throughout the nation. While the goal is to recruit 180 patients (60 metformin, 60 vitamin E, and 60 placebo), recruitment has proven to be difficult. We aim to contribute 10 patients to this 96-week treatment trial. Primary hypotheses: In pediatric nondiabetic patients with Non-Alcoholic Fatty Liver Disease (NAFLD), improvement in insulin resistance over 96 weeks of treatment with metformin will result in sustained reduction in serum alanine aminotransferase (ALT);compared to treatment with placebo In pediatric nondiabetic patients with NAFLD, improvement in oxidative stress status over 96 weeks of treatment with vitamin E will result in sustained reduction in serum ALT compared to treatment with placebo Secondary hypotheses: Treatment with metformin or vitamin E will result in sustained reduction in serum AST and GGT compared to treatment with placebo Metformin and vitamin E are equally effective in achieving histologic improvement in nondiabetic children with NAFLD Levels of proinflammatory cytokines and serum markers for fibrosis will decrease with treatment with metformin and with vitamin E compared to treatment with placebo Pediatric nondiabetic patients with NAFLD have an impaired quality of life, and these scores will improve as their serum ALT improves upon treatment with metformin or vitamin E compared to treatment with placebo Other questions to be addressed: We predict that insulin resistance is common in pediatric nondiabetic patients with NAFLD and will be significantly related to waist-to-hip ratio, waist circumference, serum ALT, and hepatic histology We predict that degree of obesity will be significantly related to hepatic histology in pediatric nondiabetic patients with NAFLD and more severe obesity (BMI or BMI z score) will be related to greater elevations in ALT and more advanced hepatic histology We predict that serum markers for steatosis, inflammation, and fibrosis will be significantly related to hepatic histology in pediatric nondiabetic patients with NAFLD We predict that worsening hepatic histology will be significantly related to a worsening in health-related quality of life in pediatric nondiabetic patients with NAFLD and more advanced histology will have worse health-related quality of life as measured by scores on the PedsQL We predict that improvement in the measures of insulin resistance will be significantly related to improvements in liver histology, serum ALT, and serum markers for steatosis, inflammation, and fibrosis in pediatric nondiabetic patients with NAFLD We predict that therapy with vitamin E will improve insulin resistance in pediatric nondiabetic patients with NAFLD We predict that improvement in liver histology upon treatment with insulin sensitizers will be significantly related to improvements in waist-to-hip ratio and waist circumference in pediatric nondiabetic patients with NAFLD We predict that therapy with same dose metformin across different age, height, and weight groups will have similar weight loss effects in pediatric nondiabetic patients with NAFLD We predict that maturation and growth (Tanner staging, anthropometric measures) will be similar across treatment groups in pediatric nondiabetic patients with NAFLD SPECIFIC AIMS: NAFLD is considered to be the most common chronic liver disease in the world. With the trend of increasing obesity throughout the world, the prevalence of Non-Alcoholic Steatohepatitis (NASH) is anticipated to increase. Currently, NASH costs society, with regards to medical resources, financial resources, and organ allocation. Finding a treatment for this disease will free up the aforementioned resources and decrease the morbidity and mortality of the affected individuals. Additionally, the treatment arm of placebo plus diet and exercise will help elucidate the natural history regarding the clinical course and histology of pediatric NASH. Subsequent studies on samples in the Specimen Repository may elucidate etio-pathogenesis of this disease. Introduction: Nonalcoholic fatty liver disease (NAFLD)is a common and increasingly recognized disorder characterized by macrovesicular accumulation of fat in hepatocytes, usually found in association with obesity, insulin resistance, and hyperlipidemia. This condition occurs in both adults and children, and arguably represents the most common cause of liver disease in pre-adolescence and adolescence. Reports from North America, Europe, Australia, and Asia highlight the global magnitude of this problem, which appears to be increasing in proportion to prevalence of pediatric obesity. Liver histology in NAFLD may demonstrate steatosis alone, to more advanced and concerning findings of fat in concert with inflammation and fibrosis Nonalcoholic steatohepatitis (NASH). Cirrhosis in the context of pediatric NASH is reported. Although noninvasive imaging is being developed to accurately quantitate hepatic fat content, no other noninvasive measures are identified to estimate degree of liver inflammation or fibrosis. Due to the fact that distinction between simple steatosis from NASH or NASH-related cirrhosis requires liver biopsy, relatively little is known in children about prevalence or natural history. With a paucity of longitudinal data, we do not know whether simple steatosis progresses to NASH, and which factors influence the rate of NASH progression to cirrhosis. Given that the location and extent of inflammation and fibrosis often differ between adult and pediatric NASH, extension of adult data to children is unwarranted. Preliminary studies are published on promising therapies for NASH. With rare exception, they are open-label, uncontrolled, non-randomized pilot trials. Most studies lack baseline or end-of-treatment biopsies, and it is unknown whether long-term treatment affects outcome. To attain adequate statistical power, multicenter studies are necessary. Realizing the need for further investigation into the natural history, pathogenesis, and treatment of adult and pediatric NASH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) issued a request for applications (RFA)in February 2001 for a multi-center network (NASH CRN). Eight Clinical Centers and a Data Coordinating Center were funded by the NIDDK, with additional support from the National Institute of Child Health and Development (NICHD) allowing expansion of the pediatric component. The NASH CRN began in the summer of 2002, and many of the protocols are being finalized and undergoing institutional review. A major effort of the network is to establish a longitudinal study of suspected or proven pediatric NAFLD cases to classify, evaluate, and follow in a standard fashion. Many of the pediatric objectives of the NASH CRN are contained within this protocol. While BCM is not a formal site of the CRN, we have been invited to participate as a site in the TONIC trial as a subcontract of St. Louis University.